Method for treating ulcers with benzoyl esters of 2-tertiary amino-1-phenyl ethanols



United States Patent 3,499,087 METHOD FOR TREATING ULCERS WITH BEN- ZOYLESTERS OF Z-TERTIARY AMINO-1- PHENYL ETHANOLS Jerome M. Glassman,Briarclilf Manor, N.Y., assignor to U.S.V. Pharmaceutical Corporation, acorporation of Delaware No Drawing. Filed May 2, 1967, Ser. No. 635,340

Int. Cl. A01n 9/24 US. Cl. 424-308 2 Claims ABSTRACT OF THE DISCLOSURECompositions containing benzoyl esters of Z-tertiaryamino-l-phenylethanols as either the free base or acid addition salts are valuable forthe treatment of ulcers. Z-diethylamino-l-phenylethy1 benzoate is thepreferred compound.

This invention relates to compositions for the treatment of ulcers andto a method of treating ulcers. In particular it relates to compositionscomprising benzoyl esters of 2- tertiary amino-l-phenyl-ethanols and theuses of said compositions in the treatment of ulcers.

The benzoyl esters of the 2-tertiary-amino-l-phenyl-ethanols have thestructure wherein R is hydrogen or lower alkoxy, such as methoxy orethoxy, and R is a secondary amino group such as pyrrolidyl, piperidyl,morphylyl, dimethylamino, diethylamino, methylethylamino, and the like,and are described in I. Am. Chem. Soc. 81, 203 (1959). Typical benzoylesters of the compositions of this invention are Compound: No.2-diethylamino-l-phenylethyl benzoate A 2-pyrro1idino-l-phenylethylbenzoate B Z-diethylamino 1 phenylethyl Z-methoxybenzoateZ-diethylamino-l-phenylethyl 2-ethoxybenzoate DZ-diethylamino-l-phenylethyl 4-ethoxybenzoate E The esters arepreferably used in the form of their pharmaceutically acceptablenon-toxic acid addition salts such as the hydrochloride, hydrobromide,phosphate, sulfate, acetate, lactate, malate, succinate, maleate,malonate, gluconic, glucuronate, benzoate, silicylate, cinnamate,mandelate, nicotinate, and the like.

The benzoyl esters of the compositions of this invention also possesstopical anesthetic activity approximating that of procaine andlidocaine. Bayer, Zentralbl. f. Inn. Med. 55, 577 (1934), unexpectedlyfound that ulcer patients given a 0.25% solution larocaine, a topicalanesthetic, orally to facilitate the passage of contrast media throughthe pylorus for radiography showed remarkable objective and subjectiveimprovement. He assumed that larocaine had a specific action on thehealing of the lesions and in this connection leaned towards the ideathat local anesthesia of a lesion or a focus of inflammation resulted inmore rapid healing.

A considerable literature has since accumulated and was reviewed in partby Lunderquist, Svenska Lakartidn 58, 15 (1961). Despite the experienceof many investigators with local anesthetics, their use for the reliefof gastroice intestinal discomfort has generally been ignored. Thevarious clinical reports detailing the complicated methods foradministration, lack of potency, inadequate duration of action,toxicity, adverse side effects have contributed to much of the lack inenthusiasm. Moreover, absence of agreement among laboratory and clinicalworkers has made this an area of controversy.

One of the most recent additions to therapy is oxethazaine. This is anextremely powerful local anesthetic. It is unusual in that it is a weakbase relatively little dissociated at gastric pH. However, Balmforth etal., Br. Med. J. 1, 355 1964), showed that oxethazaine did not improvethe capacity of an aluminum-magnesium hydroxide mixture to relieve painassociated with duodenal ulcer. There is good reason to suspect that theaction of oxethazaine is purely a surface anesthesia phenomenon. Itspain relieving potential is dependent upon direct action on nerveendings at the diseased site. Its potent spasmolytic action occurs onlyupon direct contact with the intestine; parenteral administration failsto alter contractility or tone of intestinal segments in dogs. It is,therefore, unlikely that oxethazaine acts indirectly through a neuronalcircuit.

The clinical failures reported for procaine, lidocaine and other topicalagents against ulcer pain, hypermotility, and gastric hyperacidity isattributable to the fact that they do not exist in sutficientlyundissociated form (free base) at gastric pH to be effective. Whereclinical effectiveness has been reported, the anesthetics wereadministered by perfusion of the mucosa or on the ulcer crater; thedirect contact permitted the topical action to occur before the acidityof the stomach decreased the amount of available free base. Further,presentation of anesthetic, by drip, provided a continuous supply offree base for topical action on the target site.

I have found that the benzoyl esters of theZ-tertiaryamino-l-phenyl-ethanols, particularly the benzoyl ester of2-diethylamino-l-phenyl-ethanol, used in the compositions of thisinvention have properties which make them more effective and useful inthe treatment of ulcers as compared to other topical anesthetics. Theesters of the compositions of this invention surprisingly are relativelyundissociated at an acid pH so that significant amounts of free base areavailable to penetrate the lipid sheath of nerves to affect anesthesia.This weak bacicity probably enhances the potency of the compounds in theacidic medium of the stomach.

The esters have a mild relaxing effect on the intestinal musculature.Since various gastric and intestinal disturbances frequently producehypermotility, possibly as a result of inflammation, this property is adistinct asset. Compound A also possesses mild tranquilizing action.

In addition, the esters possess anti-inflammatory activity, particularlyin reducing inflammation resulting from chronic irritation as shown bythe inhibition of granuloma formation around cotton pellets according tothe technique of Meier et al., Experientia 6, 469 (1950), as

modified by Winter et al., J. Am. Pharm. Assoc. (Sci.

ed.) 46, 515 (1957). Table I shows the antigranuloma potency of compoundA as compared to other anti-in flammatory agents.

TABLE I.ANTIGRANULOMA POTENCY Approx. ED 20 (m Although dexamethasoneand indomethacin are approximately 5-8 times more potent than compoundA, the

latter is significantly better than either hydrocortisone andphenylbutazone. For equivalent antigranuloma action, compound A appearsto exceed the potency of either hydrocortisone or phenylbutazone byfactors of 6 and 8. These findings are of particular interest since thefavorable potency of these esters in reducing inflammation resultingfrom chronic inflammation makes them more valuable in their use inanti-ulcer therapy.

The esters also alter gastric secretion and acidity.

Using both the Chay rat and restrained rat techniques, the modificationof ulcer formation by the benzoyl esters of Z-tertiaryamino-l-phenyl-ethanols has been demonstrated.

TABLE IL-INHIBITION OFRIiI iOER F RMATION-SHAY Dose (mg. Survival 1 Meantype Oompd. Admn. base/kg.) No. used (percent) ulceration Saline 35 91.4 3. lit). 3 Atropine 0. 12 100. 0 1. OiO. 5 1. 0 12 100. 0 1. 43:0. 0

Oxethazaine 0. 2 93. 3 3. 4i0. 5 Compound B 1.0 26 96. 2 1. 7i0. 4Compound A 1. 0 15 100. 0 l. 6:t=0. 4

1 Based on number surviving surgery and series of 3 injections.

2 Grading system: 0=n0r1nal stomach. l=ten or less small ulcers, 1-3 mm.diameter; 2=eleven or more small ulcers, 1-3 mm. diameter; 3=0ne or moreulcers, 4-6 mm. diameter; 4=one or more ulcers, 7+ mm. di ameter; 6=oneor more perforations of wall.

Table II shows that parenteral administrations of atropine andcompositions containing compounds A and B afford statisticallysignificant degrees of protection against rumenal ulcer formation. 1.0mg. base/kg. compound B and 1.0 mg. base/kg. compound A are about aseffective as 1.0-2.0 mg. base/kg. atropine, an anti-cholinergic agent.Oxethazaine has no inhibitory potential when administered at theestablished human therapeutic dose level.

These above studies have also indicated that administration of thecompositions of this invention orally or parenterally reduced thegastric secretion. The latter effect of these compositions were alsoshown on tests with chronic pouch dogs. Therefore, it would appear thatthe effect of the compositions proceed through a local mechanism andother mechanisms, possibly by central action.

The benzoyl esters of Z-tertiary-amino-l-phenyleth anols areadministered internally, either parenterally or orally in the solid formof tablets or capsules or in solution.

In accordance with the invention there are provided compositions for thetreatment of ulcers and methods of treating ulcers using saidcompositions. This will appear more fully irom the examples whichfollow, which are set forth by way of illustration only, and it isintended to cover all changes and modifications of examples herein whichdo not constitute departures from the spirit and scope of the invention.The examples illustrate various types of compositions coming within theinvention for a variety of administration techniques.

EXAMPLE I A composition of matter for oral administration, comprisingthe hydrochloride of 2-diethylamino-1-phenylethyl benzoate as the activeingredient in combination with a suitable carrier, was prepared bythoroughly mixing together 300 grams of the active compound and 3500grams of betalactose (milk sugar), passing the blended mixture through aNo. 40 screen and filling the mix into gelatin capsules, 450 mg. percapsule, each capsule to contain 100 mg. of active ingredient.

EXAMPLE II A composition of matter for oral administration, in tabletform, comprising the hydrochloride of Z-diethylamino-l-phenylethylbenzoate as the active ingredient in combination with a suitablecarrier, was prepared by compounding the following ingredients into atablet mix:

Grams Active ingredient 308 Sugar 308 Lactose 177 Dextrin 50 Starch 98Talcum 10 Stearic acid 10 Starch paste, q.s. to make 1000.

The above mix was compressed into tablets, weighing approximately 325mg. each tablet containing 100 mg. of active ingredient.

EXAMPLE III A composition of matter for parenteral administrationcomprising the hydrochloride of Z-diethylamino-l-phenylethyl benzoate asthe active ingredient in combination with a liquid carrier and havingthe following formula was prepared:

Grams Active ingredient 25 Benzyl alcohol 5 Water, pyrogen-free, q.s. to500 ml.

In making this solution the active ingredient was dissolved in 400 ml.of pyrogen-free water, the benzyl alcohol added, and the solution wasmade up q.s. to 500 ml.; after which the solution was filteredaseptically and filled aspectically in ampulse containing 1 ml., under anitrogen atmosphere. The resulting soltuion supplied a dosage unit of 50mg. of active ingredient.

EXAMPLE IV A liquid composition of matter for oral administrationcomprising 2 pyrrolidino-l-phenylethyl benzoate as the active ingredientin combination with a liquid carrier and having the following formulawas prepared:

Grams Active ingredient -L 25 Benzoic acid 10 Liquid sugar 35 Cherryflavor 5 Water q.s. to give a solution containing about 30 mg. of activeingredient per teaspoon.

Compositions made to contain from 5 mg. to 100 mg. per dosage unit maybe similarly prepared.

Compositions of matter similar to those in Examples I and II may be madeto include other substances having therapeutic properties useful in thetreatment of ulcers, such as pharmaceutically acceptable antacids asaluminum hydroxide, magnesium trisilicate, calcium carbonate, and thelike.

In the treatment of ulcers the benzoyl esters of the 2- tertiary-aminol-phenyl-ethanols are administered internally, either parenterally ororally in the solid form of tablets or capsules or in solution, insingle or divided doses in a range of about 1 to 10 rug/kg. daily.

I claim:

1. A process for the treatment of ulcers which comprises administeringto a host suffering from ulcers a therapeutically effective amount of acomposition in dosage unit form comprising 5 to 100 mg. of a compoundselected from the group consisting of a compound of the structurewherein R is hydrogen or lower alkoxy and R is pyrrolidyl, piperidyl,morphylyl, diethylamino, or dimethylamino, and their pharmaceuticallyacceptable, non-toxic acid addition salts, admixed with a suitablePharmaceutical carrier at a daily dose of from about 1 to 10 mg. of 5compounds per kg. of body weight of said host.

2. A process according to claim 1, wherein the compound isZ-diethylamino-l-phenylethyl benzoate.

6 References Cited Shapiro et 2.1., J. Am. Chem. Soc. 81, pp. 203-211(1959 US. Cl. X.R. 424308, 274, 267

